Mutations in the proapoptotic BAX gene are associated with defective DNA mismatch repair and altered tumor growth rates in human colon cancers

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10529-10529
Author(s):  
F. Sinicrope ◽  
R. L. Rego ◽  
A. J. French ◽  
N. R. Foster ◽  
D. J. Sargent ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Caspase 3 ◽  
Dna Mismatch Repair ◽  
Univariate Analysis ◽  
Human Colon ◽  
Wild Type ◽  
Ki 67 ◽  
Dna Mismatch ◽  
Colon Cancers ◽  
The Impact

10529 Background: BAX mutations are associated with defective DNA mismatch repair (MMR) in human colon cancers. However, the impact of BAX inactivation upon tumor cell apoptosis and proliferation in vivo remain unknown. We analyzed and compared caspase-3 and Ki-67 expression in tumors with and without BAX mutations. Methods: TNM stage II and III (n= 377) colon carcinomas were studied from participants in a 5-FU-based adjuvant therapy trial. Archival tumors were analyzed for instability at the BAT26 mononucleotide locus using polymerase chain reaction and hMLH1, hMSH2 and hMSH6 by immunohistochemistry (IHC). Frameshift mutations in a tract of eight deoxyguanosines within BAX were analyzed. Expression of caspase-3 and Ki-67 proteins were analyzed by IHC. Results: Thirty-nine of 377 (10%) tumors showed defective MMR defined as instability at BAT26 and loss of either hMLH1, hMSH2 and/or hMSH6 proteins. BAX mutations were found in 20 of 37 (54%) MMR deficient tumors and in 1 of 50 (2%) tumors with intact MMR. Mean and median number of caspase-3-positive cells were increased in tumors with defective MMR (p= 0.04), but did not differ based upon BAX status [ Table ]. However, tumors with BAX mutations showed higher Ki-67 labeling indices compared to those with wild type BAX (p= 0.01)[ Table ]. Neither BAX mutations nor caspase-3- positive cells were prognostic in a univariate analysis. Tumors with lower Ki-67 extent had improved overall survival (p=0.06), but not DFS (p=0.24). Defective MMR (vs intact) was associated with better DFS in a multivariate analysis (p= 0.03). Conclusion: MMR deficient colon cancers show frequent BAX inactivation, yet have increased apoptotic rates as indicated by increased caspase-3 expressing tumor cells. BAX mutation was associated with hyperproliferation suggesting a growth advantage compared to wild type tumors. [Table: see text] No significant financial relationships to disclose.

scholarly journals Saturation of DNA Mismatch Repair and Error Catastrophe by a Base Analogue in Escherichia coli

Genetics ◽  
2002 ◽  
Vol 161 (4) ◽  
pp. 1363-1371
Author(s):  
Kazuo Negishi ◽  
David Loakes ◽  
Roel M Schaaper
Keyword(s):  
Escherichia Coli ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Repair System ◽  
Mutagenic Action ◽  
Wild Type ◽  
Dna Mismatch ◽  
Cell Counts ◽  
Error Catastrophe ◽  
Mismatch Repair System

Abstract Deoxyribosyl-dihydropyrimido[4,5-c][1,2]oxazin-7-one (dP) is a potent mutagenic deoxycytidine-derived base analogue capable of pairing with both A and G, thereby causing G · C → A · T and A · T → G · C transition mutations. We have found that the Escherichia coli DNA mismatch-repair system can protect cells against this mutagenic action. At a low dose, dP is much more mutagenic in mismatch-repair-defective mutH, mutL, and mutS strains than in a wild-type strain. At higher doses, the difference between the wild-type and the mutator strains becomes small, indicative of saturation of mismatch repair. Introduction of a plasmid containing the E. coli mutL+ gene significantly reduces dP-induced mutagenesis. Together, the results indicate that the mismatch-repair system can remove dP-induced replication errors, but that its capacity to remove dP-containing mismatches can readily be saturated. When cells are cultured at high dP concentration, mutant frequencies reach exceptionally high levels and viable cell counts are reduced. The observations are consistent with a hypothesis in which dP-induced cell killing and growth impairment result from excess mutations (error catastrophe), as previously observed spontaneously in proofreading-deficient mutD (dnaQ) strains.

scholarly journals Intertumoral Heterogeneity of CD3+ and CD8+ T-Cell Densities in the Microenvironment of DNA Mismatch-Repair–Deficient Colon Cancers: Implications for Prognosis

2018 ◽  
Vol 25 (1) ◽  
pp. 125-133 ◽  
Author(s):  
Harry H. Yoon ◽  
Qian Shi ◽  
Erica N. Heying ◽  
Andrea Muranyi ◽  
Joerg Bredno ◽  
...  
Keyword(s):  
T Cell ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Cd8 T Cell ◽  
Dna Mismatch ◽  
Colon Cancers ◽  
Cell Densities

Model-based prediction of defective DNA mismatch repair using clinicopathological variables in stage II and III colon cancers

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 11093-11093
Author(s):  
A. J. French ◽  
F. Sinicrope ◽  
N. R. Foster ◽  
S. N. Thibodeau ◽  
D. J. Sargent ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Histologic Grade ◽  
Important Predictor ◽  
Stage Ii ◽  
Tumor Site ◽  
Dna Mismatch ◽  
Colon Cancers ◽  
And Gender

11093 Background: Defective DNA mismatch repair (MMR) results in microsatellite instability (MSI) and is detected in approximately 15% of sporadic colon cancers. MMR status has been shown to provide prognostic and predictive information in primary colon cancers. We sought to develop a model to predict MMR deficiency using clinically available data, and thereby facilitate patient selection for MMR or MSI testing. Methods: TNM stage II and III colon carcinomas (n= 982) were studied from six 5- fluorouracil-based adjuvant therapy trials conducted by the North Central Cancer Treatment Group. MMR status in tumors had been analyzed by MSI (using mono- and dinucleotide markers) or by immunohistochemistry for MMR proteins (hMLH1 and hMSH2). Logistic regression and a recursive partitioning and amalgamation (RPA) analysis was used to identify important predictive factors of MMR status. Factors explored included age, gender, histologic grade, tumor site, stage, lymph node metastases, and T-stage. Results: Defective MMR was found in147 (15%) cancers. Tumor site was the most important predictor of MMR status followed by histologic grade. Distal tumors had a low likelihood of defective MMR (3% rate overall; 13/468), whereas proximal tumors had a greater likelihood of defective MMR (26%; 130/506). For patients with proximal tumors, the addition of histologic grade and gender increased the prediction of defective MMR ( Table ). Using tumor site, histologic grade, and gender, the logistic regression model showed excellent discrimination (c- statistic = 0.81). Conclusions: Tumor site is an important predictor of defective MMR that is rare in distal and increased in proximal tumors. The combination of proximal site, poor differentiation, and female gender resulted in a 51% likelihood of defective MMR. Therefore, this model can facilitate the selection of sporadic colon cancers for MMR or MSI testing to enable its use in clinical decision-making. [Table: see text] No significant financial relationships to disclose.

scholarly journals DNA Mismatch Repair in Eukaryotes and Bacteria

2010 ◽  
Vol 2010 ◽  
pp. 1-16 ◽  
Author(s):  
Kenji Fukui
Keyword(s):  
Mismatch Repair ◽  
Molecular Mechanisms ◽  
Dna Mismatch Repair ◽  
Repair System ◽  
Dna Mismatch ◽  
Replication Errors ◽  
Colon Cancers ◽  
Basic Features ◽  
Almost All ◽  
Dna Replication Errors

DNA mismatch repair (MMR) corrects mismatched base pairs mainly caused by DNA replication errors. The fundamental mechanisms and proteins involved in the early reactions of MMR are highly conserved in almost all organisms ranging from bacteria to human. The significance of this repair system is also indicated by the fact that defects in MMR cause human hereditary nonpolyposis colon cancers as well as sporadic tumors. To date, 2 types of MMRs are known: the human type andEscherichia colitype. The basic features of the former system are expected to be universal among the vast majority of organisms including most bacteria. Here, I review the molecular mechanisms of eukaryotic and bacterial MMR, emphasizing on the similarities between them.

Detecting deficient DNA mismatch repair in stage II and III colon cancers.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 419-419
Author(s):  
F. Sinicrope ◽  
P. Benatti ◽  
N. R. Foster ◽  
S. Marsoni ◽  
G. Monges ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Histologic Grade ◽  
Stage Ii ◽  
Lymph Node Status ◽  
Tumor Site ◽  
Dna Mismatch ◽  
Colon Cancers ◽  
Mmr Deficiency

419 Background: Deficient DNA mismatch repair (MMR) results in microsatellite instability (MSI) that is detected in ∼15% of sporadic colon cancers. MMR status has been shown to provide prognostic and predictive information. We developed a model to predict MMR deficiency using clinically available data, and thereby facilitate the selection of patient tumors for MMR testing. Methods: Data were utilized from stage II and III colon carcinoma patients (n = 2016) who participated in 5-fluorouracil-based adjuvant studies (NCCTG, FFCD, NCIC, GIVIO, NSABP) and an Italian cohort. MMR status in tumors had been determined by MSI testing or by immunohistochemistry for hMLH1 and hMSH2 proteins. Logistic regression and a recursive partitioning and amalgamation analysis was used to identify factors (histologic grade, gender, tumor site, stage, age, lymph node status, T-stage) predictive of MMR status. Results: Of the cancers, 357 (17.7%) showed deficient MMR. Tumor site was the most important predictor of MMR status followed by histologic grade, then stage (II vs. III) and then gender. Distal tumors had a low likelihood of deficient MMR (5% rate overall), whereas proximal tumors had a greater likelihood of deficient MMR (30%). For patients with proximal tumors, the addition of histologic grade and stage increased the prediction of deficient MMR (Table). Using tumor site, histologic grade, and stage, the logistic regression model showed excellent discrimination (c-statistic = 0.80). Conclusions: Routine clinicopathological data can facilitate the identification of MMR deficient cases. Tumor site and histologic grade were the strongest predictors of MMR deficiency. Within proximal, poorly differentiated tumors, stage was highly predictive. These findings suggest that our model can assist in selecting sporadic colon cancers for MMR testing for use in clinical decision-making, especially for stage II patients. [Table: see text] [Table: see text]

scholarly journals Differential Radiosensitization in DNA Mismatch Repair-Proficient and -Deficient Human Colon Cancer Xenografts with 5-Iodo-2-pyrimidinone-2′-deoxyribose

2004 ◽  
Vol 10 (22) ◽  
pp. 7520-7528 ◽  
Author(s):  
Yuji Seo ◽  
Tao Yan ◽  
Jane E. Schupp ◽  
Valdir Colussi ◽  
Kerri L. Taylor ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Human Colon ◽  
Human Colon Cancer ◽  
Dna Mismatch

Aspirin increases the expression of dna mismatch repair proteins in human colon cancer cells

2000 ◽  
Vol 118 (4) ◽  
pp. A656 ◽  
Author(s):  
Ajay Goel ◽  
Dong K Chang ◽  
Luigi Ricciardiello ◽  
Dharam P Chauhan ◽  
C. Richard Boland
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Human Colon ◽  
Colon Cancer Cells ◽  
Human Colon Cancer ◽  
Dna Mismatch ◽  
Mismatch Repair Proteins ◽  
Human Colon Cancer Cells

Maternal Effect for DNA Mismatch Repair in the Mouse

Genetics ◽  
2002 ◽  
Vol 160 (1) ◽  
pp. 271-277
Author(s):  
Vanessa E Gurtu ◽  
Shelly Verma ◽  
Allie H Grossmann ◽  
R Michael Liskay ◽  
William C Skarnes ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Maternal Effect ◽  
Genome Stability ◽  
Germ Line ◽  
Dna Mismatch Repair ◽  
Surprising Result ◽  
Wild Type ◽  
Repair Gene ◽  
Dna Mismatch ◽  
Dna Repair Gene

Abstract DNA mismatch repair (DMR) functions to maintain genome stability. Prokaryotic and eukaryotic cells deficient in DMR show a microsatellite instability (MSI) phenotype characterized by repeat length alterations at microsatellite sequences. Mice deficient in Pms2, a mammalian homolog of bacterial mutL, develop cancer and display MSI in all tissues examined, including the male germ line where a frequency of ~10% was observed. To determine the consequences of maternal DMR deficiency on genetic stability, we analyzed F1 progeny from Pms2−/− female mice mated with wild-type males. Our analysis indicates that MSI in the female germ line was ~9%. MSI was also observed in paternal alleles, a surprising result since the alleles were obtained from wild-type males and the embryos were therefore DMR proficient. We propose that mosaicism for paternal alleles is a maternal effect that results from Pms2 deficiency during the early cleavage divisions. The absence of DMR in one-cell embryos leads to the formation of unrepaired replication errors in early cell divisions of the zygote. The occurrence of postzygotic mutation in the early mouse embryo suggests that Pms2 deficiency is a maternal effect, one of a limited number identified in the mouse and the first to involve a DNA repair gene.

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